Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors.

BACKGROUND: The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated. METHODS: A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography. RESULTS: Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease. CONCLUSIONS: Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors.

Recombinant human thyroid-stimulating hormone as an alternative for thyroid hormone withdrawal in thyroid cancer management.

PURPOSE OF REVIEW: The purpose of the review is to summarize the current findings of using recombinant human thyroid-stimulating hormone (rhTSH, also known as Thyrogen) as adjuvant stimulation for diagnostic monitoring, thyroid remnant ablation, and treatment of metastatic thyroid cancer. RECENT FINDINGS: A negative Thyrogen-stimulated thyroglobulin level has a negative predictive value of up to 98.5%. Therefore, it is unnecessary to repeat a Thyrogen-stimulated thyroglobulin level in the surveillance of patients with a negative result. There are no significant differences found in the rate of recurrence or persistent disease between Thyrogen-assisted and thyroid hormone withdrawal-ablated patient groups. Studies have shown that rapid clearance of excess radioiodine from the body in the euthyroid state with Thyrogen stimulation has significantly reduced whole body radiation exposure as compared with the hypothyroid state in withdrawal patients. SUMMARY: Thyrogen-assisted diagnosis and radioiodine ablation of thyroid remnant provide a reliable tool in the management of thyroid cancer without sacrificing patient quality of life. We believe that the use of Thyrogen for radioiodine treatment of metastatic thyroid cancer may also provide a better option due to its rapid preparation time and safety. Further prospective studies are required for the assessment of long-term outcomes.

Diagnostic accuracy of 18F-FDG PET in restaging patients with medullary thyroid carcinoma and elevated calcitonin levels.

UNLABELLED: Medullary thyroid carcinoma (MTC) is a rare endocrine tumor arising from the C-cells of the thyroid gland. Calcitonin is the principal serum tumor marker. A rising calcitonin level after total thyroidectomy for localized disease generally indicates residual, recurrent, or metastatic disease. The role of (18)F-FDG PET in MTC remains somewhat unclear. We reviewed our own experience with (18)F-FDG PET in postthyroidectomy MTC patients with elevated calcitonin. METHODS: From our database, we identified patients with suspected residual, recurrent, or metastatic MTC and elevated calcitonin who had been referred for (18)F-FDG PET between January 2000 and October 2005. (18)F-FDG PET findings were classified as positive or negative on the basis of visual interpretation of the scan. Standardized uptake values (SUVs) were also calculated. The (18)F-FDG PET findings were verified by histopathologic examination, when available, or other imaging studies and clinical follow-up. Any negative (18)F-FDG PET result was considered false-negative. RESULTS: Twenty-eight patients underwent a total of 38 (18)F-FDG PET studies. Calcitonin levels ranged from 106 to 541,000 pg/mL (median, 7,260 pg/mL). There were 23 true-positive, 1 false-positive, and 14 false-negative (18)F-FDG PET scans, yielding an overall sensitivity of 62%. There was no true-positive finding when calcitonin levels were below 509 pg/mL (n = 5). Using an arbitrary cutoff of 1,000 pg/mL, we found that the sensitivity in scans with calcitonin levels greater than 1,000 pg/mL increased to 78% (21/27; 95% confidence interval, 58%-91%). The mean SUV of all lesions with (18)F-FDG uptake was 5.3 +/- 3.2 (range, 2.0-15.9). Among the 14 patients with false-negative (18)F-FDG PET findings, 8 had concurrent anatomic imaging studies and only 2 of these had positive findings. CONCLUSION: (18)F-FDG PET can detect residual, recurrent, or metastatic MTC with a reasonable sensitivity of 78% when the calcitonin level is above 1,000 pg/mL but appears of limited use if the calcitonin level is below 500 pg/mL.

Phase II Study of Modified FOLFOX6 With Bevacizumab in Metastatic Gastroesophageal Adenocarcinoma.

BACKGROUND: The median survival for patients with metastatic gastroesophageal adenocarcinoma is <12 months. Bevacizumab has demonstrated promising activity in metastatic gastroesophageal adenocarcinoma when used in combination with cisplatin-based regimens for patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of bevacizumab in combination with the oxaliplatin-based regimen, modified FOLFOX6, in patients with metastatic gastroesophageal adenocarcinoma. METHODS: Patients with untreated metastatic adenocarcinoma of the stomach, gastroesophageal junction, or distal esophagus received mFOLFOX6 (leucovorin 400 mg/m, fluorouracil 400 mg/m bolus and 2400 mg/m continuous infusion over 46 h, oxaliplatin 85 mg/m) and bevacizumab (10 mg/kg) every 2 weeks until disease progression or intolerance. Response by RECIST was evaluated by CT scan every 8 weeks. The primary objective was progression-free survival (PFS); secondary objectives were safety, response rate, and overall survival (OS). RESULTS: A total of 39 patients with untreated metastastic gastroesophageal adenocarcinoma were enrolled between September 2008 and June 2012. Median number of cycles administered was 12 (range, 4 to 86). The confirmed response rate was 56.4% (3 complete response and 19 partial response). The median PFS was 7.8 months and median OS was 14.7 months. Three patients remain on treatment, and 11 patients are alive, of whom 6 have survived >24 months. Treatment-related grade 3/4 toxicities included neutropenia (33.3%), neuropathy (20.5%), thromboembolism (VTE) (7.7%), thrombocytopenia (7.7%), anemia (2.6%), hypertension (2.6%), and proteinuria (2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. CONCLUSIONS: First-line mFOLFOX6 with bevacizumab for metastatic gastroesophageal adenocarcinoma was well tolerated and associated with longer PFS and OS compared with historical data from similar populations treated without bevacizumab. Our results suggest that the addition of bevacizumab to mFOLFOX6 may provide clinical benefit in American patients with metastatic gastroesophageal adenocarcinoma, a finding consistent with previous studies of first-line bevacizumab in combination with chemotherapy for this disease.

The utility of I-123 pretherapy scan in I-131 radioiodine therapy for thyroid cancer.

BACKGROUND: There is a growing belief that a pretherapy scan yields little or no additional information that would impact on radioiodine ablation dosing. In addition, there is some concern regarding on the stunning effect of a pretherapy scan, especially when I-131 radioisotope is used for imaging. We hypothesized that a pretherapy scan provides invaluable information on the amount of thyroid remnant, sometimes indicating the need for two-step I-131 ablation. It may also detect unsuspected local lymph node involvement or distant metastases, indicating the requirement for a higher I-131 dose after thyroidectomy. The aim of this study was to evaluate how effective pretherapy scans are for guiding I-131 therapy planning and augmenting information provided in the pathology reports for thyroidectomy specimens. METHODS: We reviewed 122 patients who underwent I-123 pretherapy scan and I-131 radioablation at Yale New Haven Hospital between January 2006 and August 2007. The percentage of neck uptake and whole-body images were acquired 24 hours following the administration of 51.8 MBq (1.4 mCi) of I-123 NaI. A 24-hour uptake of >3% was used as the cutoff to determine whether there was a greater than desired quantity of thyroid remnant, which would require a two-step treatment protocol. Furthermore, attention was paid to identifying cervical lymph nodes, which may not have presented themselves in the euthyroid state at the time of thyroidectomy. Additional clinical information provided by pretherapy scans was computed as percentages with 95% confidence intervals by using adjusted Wald intervals. RESULTS: Overall, the pretherapy scans provided additional critical information in 25% of the cases (31/122; 95% CI: 18%-34%). For cases demonstrating >3% uptake with midline lymph nodes, the pretherapy scan provided additional information in 50% of the cases (8/16; 95% CI: 28%-72%). CONCLUSIONS: Our study demonstrated that I-123 pretherapy scans provide valuable information with regard to unsuspected lymph nodes or distant metastases, indicating the requirement for a significantly higher I-131 dose, and unexpected large thyroid remnants, suggesting the need for two-step ablation. We should take advantage of stimulated pretherapy scans and adjust the treatment dosing accordingly.

Targeted radionuclide therapy.

Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.